This invention pertains to novel, substantially enantiomerically pure bis-phosphine compounds possessing the unique feature of having both a carbon-bonded phosphine and a nitrogen-bonded phosphine connected by a divalent chiral group. The compounds are useful as ligands for metal catalysts for asymmetric reactions and have demonstrated surprising stability as well as excellent results, in particular as rhodium complexes for asymmetric hydrogenation. This invention also pertains to novel processes and intermediate compounds useful for the preparation of the bis-phosphine compounds and to compounds comprising one or more of the bis-phosphine compounds in complex association with one or more Group VIII metals and their use for asymmetric hydrogenation.
Asymmetric catalysis is the most efficient method for the generation of products with high enantiomeric purity, as the asymmetry of the catalyst is multiplied many times over in the generation of the chiral product. These chiral products have found numerous applications as building blocks for single enantiomer pharmaceuticals as well as in some agrochemicals. The asymmetric catalysts employed can be enzymatic or synthetic in nature. The latter types of catalyst have much greater promise than the former due to much greater latitude of applicable reaction types. Synthetic asymmetric catalysts are usually composed of a metal reaction center surrounded by an organic ligand. The ligand usually is generated in high enantiomeric purity, and is the agent inducing the asymmetry. These ligands are, in general, difficult to make and therefore expensive.
As is described by Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998, 9, 2377-2407, asymmetric ferrocene derivatives have found great utility as ligands for asymmetric catalysis in reactions as varied as asymmetric hydrogenations, asymmetric Aldol reactions, asymmetric organometallic additions, and asymmetric hydrosilations. These ferrocene species usually are bidentate in nature, using a variety of ligating species. In the cases where the ligands are phosphines they invariably are carbon-linked phosphines. In no cases do these ferrocene-based ligands have heteroatom linkage to the phosphorus atom. Fiorini, M. and Giongo, G. M. J. Mol. Cat. 1979, 5, 303-310, and Pracejus, G.; Pracejus, H. Tetrahedron Lett. 1977, 3497-3500, report that bis-aminophosphine-based asymmetric ligands afford moderate results for asymmetric hydrogenations ( less than 90% enantiomeric excessxe2x80x94ee), but in no cases have these ligands had either a metallocenyl moiety or a mixture of carbon and nitrogen-bonded phosphines included therein. Indeed, there appear to be no reports of chiral, non-racemic, bis-phosphine ligands where one phosphine is bonded to three carbon atoms and the other is bonded to two carbons and one nitrogen.
The novel bis-phosphine compounds provided by our invention are substantially enantiomerically pure bis-phosphine compounds comprising a substantially enantiomerically pure chiral backbone linking two phosphine residues wherein one of the phosphine residues has three phosphorus-carbon bonds and the other phosphine residue has two phophorus-carbon bonds and one phosphorus-nitrogen bond wherein the nitrogen is part of the chiral backbone. These compounds are the first examples of chiral bis-phosphines combining a tri-hydrocarbylphosphine with a dihydrocarbylaminophosphine. These species can be utilized as bidentate ligands for asymmetric catalysis for a variety of reactions. They are of particular interest for asymmetric hydrogenations, and as the rhodium complex they have afforded hydrogenation products with high enantiomeric excess, in particular for the rhodium-catalyzed hydrogenation of prochiral olefins and ketones. The activity of these compounds is readily modified by the choice of the amine substituents.
We have discovered a broad group of novel substantially enantiomerically pure bis-phosphine compounds comprised of one phosphine residue having three phosphorus-carbon bonds and the other having two phosphorus-carbon bonds and one phosphorus-nitrogen bond. Examples of the substantially enantiomerically pure, i.e., an enantiomeric excess of 90% or greater, compounds include phosphinometallocenylaminophosphines having the general formulas 1 and 2 (the enantiomer of 1): 
wherein
R is selected from substituted and unsubstituted, branched- and straight-chain C1-C20 alkyl, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted C6-C20 carbocyclic aryl, and substituted and unsubstituted C4-C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
R1, R2, R3, R4, and R5 are independently selected from hydrogen, substituted and unsubstituted, branched- and straight-chain C1-C20 alkyl, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted C6-C20 carbocyclic aryl, and substituted and unsubstituted C4-C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
n is 0 to 3;
m is 0 to 5; and
M is selected from the metals of Groups IVB, VB, VIB, VIIB and VIII.
The alkyl groups which may be represented by each of R, R1, R2, R3, R4, and R5 may be straight- or branched-chain, aliphatic hydrocarbon radicals containing up to about 20 carbon atoms and may be substituted, for example, with one to three groups selected from C1-C6-alkoxy, cyano, C2-C6-alkoxycarbonyl, C2-C6-alkanoyloxy, hydroxy, aryl and halogen. The terms xe2x80x9cC1-C6-alkoxyxe2x80x9d, xe2x80x9cC2-C6-alkoxycarbonylxe2x80x9d, and xe2x80x9cC2-C6-alkanoyloxyxe2x80x9d are used to denote radicals corresponding to the structures xe2x80x94OR6, xe2x80x94CO2 R6, and xe2x80x94OCOR6, respectively, wherein R6 is C1-C6-alkyl or substituted C1-C6-alkyl. The term xe2x80x9cC3-C8-cycloalkylxe2x80x9d is used to denote a saturated, carbocyclic hydrocarbon radical having three to eight carbon atoms. The aryl groups which each of R, R1, R2, R3, R4, and R5 may represent may include phenyl, naphthyl, or anthracenyl and phenyl, naphthyl, or anthracenyl substituted with one to three substituents selected from C1-C6-alkyl, substituted C1-C6-alkyl, C6-C10 aryl, substituted C6-C10 aryl, C1-C6-alkoxy, halogen, carboxy, cyano, C1-C6-alkanoyloxy, C1-C6-alkylthio, C1-C6-alkylsulfonyl, trifluoromethyl, hydroxy, C2-C6-alkoxycarbonyl, C2-C6-alkanoylamino and xe2x80x94Oxe2x80x94R7, Sxe2x80x94R7xe2x80x94SO2xe2x80x94R7, xe2x80x94NHSO2R7 and xe2x80x94NHCO2R7, wherein R7 is phenyl, naphthyl, or phenyl or naphthly substituted with one to three groups selected from C1-C6-alkyl, C6-C10 aryl, C1-C6-alkoxy and halogen.
The heteroaryl radicals include a 5- or 6-membered aromatic ring containing one to three heteroatoms selected from oxygen, sulfur and nitrogen. Examples of such heteroaryl groups are thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl and the like. The heteroaryl radicals may be substituted, for example, with up to three groups such as C1-C6-alkyl, C1-C6-alkoxy, substituted C1-C6-alkyl, halogen, C1-C6-alkylthio, aryl, arylthio, aryloxy, C2-C6-alkoxycarbonyl and C2-C6-alkanoylamino. The heteroaryl radicals also may be substituted with a fused ring system, e.g., a benzo or naphtho residue, which may be unsubstituted or substituted, for example, with up to three of the groups set forth in the preceding sentence. The term xe2x80x9chalogenxe2x80x9d is used to include fluorine, chlorine, bromine, and iodine.
The compounds of the invention which presently are preferred have formulas 1 and 2 wherein R is C, to C6 alkyl; R1 is hydrogen or C1 to C6 alkyl; R2 is aryl (preferably phenyl), ethyl, isopropyl, or cyclohexyl; R3 is aryl, most preferably phenyl; R4 and R5 are hydrogen; and M is iron, ruthenium, or osmium, most preferably iron.
The compounds of our invention contain both a carbon-linked and a nitrogen-linked phosphine. This mixture of features is not known in the literature (and is particularly not known for metallocene-based ligands) and affords a different electronic environment when complexed to a catalyst metal center as compared to other ligands. In addition, the metallocene-based ligands are readily modifiable by varying R1 according to the choice of the amine used, and thus allow simple modification of the reactivity and selectivity of the catalyst prepared from these ligands. An unexpected but particularly advantageous characteristic of this metallocene-based phosphino-aminophosphine structural class is their resistance to oxidative degradation. Indeed, these types of compounds retain activity and enantioselectivity (as demonstrated by both physical properties and trial reactions of their metal complexes) over extended periods at ambient temperature in an air atmosphere, conditions under which many phosphines oxidize to the inactive phosphine oxides.
Our invention also provides novel processes for the preparation of compounds of formulas 1 and 2. Thus, one embodiment of the processes of the present invention involves a process for the preparation of a substantially enantiomerically pure compound having formula 1: 
which comprises the steps of:
(1) contacting a dialkyl amine having formula 3: 
xe2x80x83with a carboxylic anhydride having the formula (R10CO)2O to obtain an ester compound having formula 4: 
(2) contacting the ester produced in step (1) with an amine having the formula H2Nxe2x80x94R1 to obtain an intermediate amino-phosphine compound having formula 5: 
(3) contacting intermediate compound 5 with a halophosphine having the formula Xxe2x80x94P(R2)2;
wherein R, R1, R2, R3, R4, R5, n, m, and M are defined hereinabove, R8 and R9 are independently selected from substituted and unsubstituted, branched- and straight-chain C1-C20 alkyl, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted C6-C20 carbocyclic aryl, and substituted and unsubstituted C4-C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen, R10 is a C1 to C4 alkyl radical, and X is chlorine, bromine, or iodine. The compounds of formula 2 may be prepared when dialkylamine having formula 6: 
is used as the starting material affording intermediates 7 and 8 analogous to 4 and 5, respectively. 
In the first step of the process, dialkylamine reactant compound 3 is contacted with a carboxylic anhydride. The amount of anhydride used may be about 1 to 100 moles, preferably about 2 to 10 moles, per mole of dialkylamine reactant 3. Although the carboxylic anhydride may contain up to about 8 carbon atoms, acetic anhydride is particularly preferred. The first step of the process may be carried out at a temperature between about 20xc2x0 C. and the boiling point of the anhydride, preferably about 80 to 120xc2x0 C. While an inert solvent may be used in step (1), such a solvent is not essential and the carboxylic anhydride may function as both solvent and reactant. At the completion of the first step, the ester intermediate may be isolated for use in the second step by conventional procedures such as crystallization or removing the carboxylic anhydride and any extraneous solvent present, e.g., by distillation.
Dialkylamine reactant compounds 3 can be prepared in high enantiomeric purity by several known methods. For example, precursor 9 having the formula: 
can be prepared in high enantiomeric purity using the procedures described by Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J. Am. Chem. Soc. 1970, 92, 5389-5393; Armstrong, D. W.; DeMond, W.; Czech, B. P. Anal. Chem. 1985, 57, 481-484; and Boaz, N. W. Tetrahedron Letters 1989, 30, 2061-2064. Precursor 9 then can be converted by known procedures to dialkylamine reactant 3, e.g., using the procedures described in Hayashi, T. et al. Bull Chem. Soc. Jpn. 1980, 53, 1130-1151; and the references mentioned in the preceding sentence. The enantiomeric species 6 can be prepared in a like manner.
In the second step of the process, the ester intermediate obtained from step (1) is contacted and reacted with an amine having the formula H2NR1 in the presence of a C1 to C4 alkanol solvent, preferably methanol or 2-propanol. The second step may be carried out at a temperature between 20xc2x0 C. and the boiling point of the solvent, preferably about 25 to 50xc2x0 C. The mole ratio of the amine:ester intermediate 4 (or 7) typically is in the range of about 1:1 to 25:1. Intermediate 5 (or 8) may be recovered for use in step (3) by conventional procedures such as extractive purification or crystallization.
In the third step of our novel process, intermediate 5 (or 8) is contacted and reacted with a halophosphine of the formula XPR22 wherein X is chlorine, bromine, or iodine using a halophosphine:intermediate 5 (or 8) mole ratio in the range of about 0.8:1 to 1.3:1. The reaction of step (3) is carried out in the presence of an acid acceptor such as a tertiary amine, e.g., trialkylamines containing a total of 3 to 15 carbon atoms, pyridine, substituted pyridines and the like. The amount of acid acceptor used normally is at least 1 mole of acid acceptor per mole of halophosphine employed and up to 5 moles of acid acceptor per mole of halophosphine. Step (3) is carried out in the presence of an inert solvent. Examples of inert solvents include, but are not limited to, non-polar, aprotic solvents such as aliphatic and aromatic hydrocarbons containing 6 to 10 carbon atoms, e.g., hexane, heptane, octane, toluene, the various xylene isomers and mixtures thereof, and the like; halogenated, e.g., chlorinated, hydrocarbons containing up to about 6 carbon atoms such as dichloromethane, chloroform, tetrachloroethylene, chorobenzene and the like; and cyclic and acyclic ethers containing from about 4 to 8 carbon atoms, e.g., tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like. The acid acceptor and solvent particularly preferred are triethylamine and toluene, respectively. Step (3) may be carried out at a temperature between about xe2x88x9220xc2x0 C. and the boiling point of the solvent, preferably about 0 to 30xc2x0 C.
Intermediate amino-phosphine compounds 5 and 8 are novel compounds and constitute an additional embodiment of our invention. Also included within the scope of the present invention are catalytically-active compounds comprising one or more substantially enantiomerically pure, bis-phosphine compounds comprising a substantially enantiomerically pure chiral backbone linking two phosphine residues wherein one of the phosphine residues has three phosphorus-carbon bonds and the other phosphine residue has two phophorus-carbon bonds and one phosphorus-nitrogen bond wherein the nitrogen is part of the chiral backbone in complex association with one or more Group VIII metals, preferably rhodium, iridium or ruthenium.